Egr-1 and EtOH-induced hepatic leukocyte recruitment

描述(申请人提供)：长期接触酒精会导致肝脏损伤。我们的实验室已经证明Egr-1在早期酒精性肝损伤的发生发展中是必不可少的。EGR-1直接或间接调节黏附分子ICAM-1和趋化因子MCP-1和MIP-2，它们在炎症过程中都对白细胞重新聚集到肝脏起重要作用。由于慢性乙醇促进了内毒素刺激的Egr-1的表达，我们推测Egr-1的增加调节了ICAM-1、MCP-1和MIP-2的表达，并参与了早期乙醇诱导的肝损伤。这项提议的具体目的将决定(1)Egr-1是否调节ICAM-1、MCP-1和MIP-2的表达，以及(2)这些基因在慢性酒精喂养后在哪些细胞类型中表达。EGR-1是介导组织缺血损伤的炎性基因的主要调节因子。我们的研究结果将有助于我们理解Egr-1是否在酒精性肝损伤中作为基因表达的主开关，因此可能成为酒精性肝损伤治疗干预的新靶点。

DESCRIPTION (provided by applicant): Chronic ethanol exposure can lead to hepatic injury. Our lab has demonstrated that Egr-1 is essential for the development of early, ethanol-induced liver injury. Egr-1 either directly or indirectly regulates the adhesion molecule ICAM-1 and the chemokines MCP-1 and MIP-2, each of which is important for leukocyte recruitment to the liver during inflammation. Because chronic ethanol enhances LPS-stimulated Egr-1 expression, we hypothesize that increased Egr-1 regulates ICAM-1, MCP-1 and MIP-2 expression and contributes to early ethanol-induced liver injury. The Specific Aims of this proposal will determine (1) if Egr- 1 regulates ICAM-1, MCP-1 and MIP-2 expression and (2) in which cell types these genes are expressed after chronic ethanol feeding. Egr-1 functions as a master regulator of inflammatory genes mediating tissue damage in ischemia. Results of our studies will contribute to our understanding of whether Egr-1 acts as a 'master switch' for gene expression in ethanol-induced liver injury and therefore may be a novel target for therapeutic intervention in ethanol-induced liver injury.